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HAL Id: inserm-00194081

https://www.hal.inserm.fr/inserm-00194081

Submitted on 5 Dec 2007

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persons with anxiety disorders: Evidence from a

population study of diurnal cortisol changes.

Isabelle Chaudieu, Isabelle Beluche, Joanna Norton, Jean-Philippe Boulenger,

Karen Ritchie, Marie-Laure Ancelin

To cite this version:

Isabelle Chaudieu, Isabelle Beluche, Joanna Norton, Jean-Philippe Boulenger, Karen Ritchie, et al.. Abnormal reactions to environmental stress in elderly persons with anxiety disorders: Evidence from a population study of diurnal cortisol changes.. Journal of Affective Disorders, Elsevier, 2008, 106 (3), pp.307-13. �10.1016/j.jad.2007.07.025�. �inserm-00194081�

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Abnormal reactions to environmental stress in elderly persons with anxiety disorders: evidence from a population study of diurnal cortisol changes.

Running title: cortisol in elderly persons with anxiety disorders

Isabelle CHAUDIEUa§, Isabelle BELUCHEa§, Joanna NORTONa, Jean-Philippe

BOULENGERa,b, Karen RITCHIEa, Marie Laure ANCELINa,*

a

Inserm, U888, Montpellier, F-34093 France ; Univ Montpellier1, Montpellier, F-34000 France ;

b

CHU Montpellier, Hop La Colombiere/ Department of Adult Psychiatry, Montpellier, F-34093

France.

§The two first authors contributed equally to this work

*

corresponding author:

Inserm U888, La Colombière Hospital, pav 42,

39 Avenue Flahault, BP 34493, 34093 Montpellier Cedex 5, France

ancelin@montp.inserm.fr

Tel: 4 99 61 45 62; Fax: 4 99 61 45 79

HAL author manuscript inserm-00194081, version 1

Journal of Affective Disorders 2007;:epub ahead of print

HAL author manuscript inserm-00194081, version 1

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ABSTRACT

Background: Cortisol secretion in elderly persons with anxiety disorders exposed to common

stressful situations has not been evaluated.

Methods: Salivary-free cortisol levels were evaluated at 8, 15, and 22h, in 201 elderly subjects

during stressful and non-stressful days. Psychiatric symptomatology was assessed by a

standardized psychiatric examination (MINI).

Results: Elderly subjects without psychiatric disorder showed a sustained increase in cortisol

secretion several hours after the exposure to a stressful situation. In comparison, subjects with

anxiety disorders showed a greater increase in cortisol secretion in the stressful situation, with

lowered recuperation capacity. This effect was dose-dependent as a function of anxiety

co-morbidity. Persons reporting lifetime major trauma with intrusions exhibited lowered continuous

basal cortisol associated with efficient recuperation capacity. Independently of psychopathology,

women appeared more reactive to stressful environmental conditions.

Limitations: Exclusion of institutionalized persons and benzodiazepine users may have led to

sampling of less severe anxiety symptoms.

Conclusions: Dysregulation of the hypothalamic-pituitary-adrenal axis was observed in elderly

persons with anxiety disorders experiencing environmental stress. A common pattern of

up-regulated diurnal cortisol secretion was observed in anxious subjects with lifetime and current

anxiety disorder irrespective of sub-type (generalized anxiety, phobias) suggesting a stable trait

and a common “core” across disorders. Elderly persons who had experienced trauma with

subsequent intrusions showed a distinct pattern with down-regulated activity.

Key words: HPA axis, stress, anxiety disorders, traumatism, elderly.

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1. Introduction

Generalized anxiety disorder (GAD) and phobia are frequent in the general population

(Krasucki et al., 1998). Some experimental studies in young adults have linked these disorders to

underlying changes in the hypothalamic-pituitary-adrenal (HPA) axis, resulting in an abnormal

response (hypercortisolemia) to acute stress (Alpers et al., 2003; Condren et al., 2002; Furlan et

al., 2001) but not consistently (Connor and Davidson, 1998; Young et al., 2004a)). This variability

may be attributable to the nature and duration of the stressors (Glynn et al., 2002; Haynes et al.,

1991).

Elderly persons are exposed to higher rates of life events than younger adults. Their

biological response to experimental stress may be prolonged (Deuschle et al., 1997; Van Cauter et

al., 1996; Wilkinson et al., 2001) suggesting modifications to underlying stress physiology.

Previous experimental studies have generally used artificial, acute stimuli to induce stress, so little

is known about cortisol secretion in naturalistic conditions especially in the more vulnerable group

of elderly persons with anxiety disorders. The present study investigates diurnal cortisol secretion

in a community cohort exposed to continuous low-grade naturalistic stress (a half-day hospital

visit) contrasted with a quiet day at home as a function of anxiety disorder.

2. Methods

2.1. Study population

Subjects (n=261) were selected by random sampling from the electoral roles (Ritchie et al.,

2004), excluding cases of dementia and persons being treated with medication likely to modify

cortisol levels (glucocorticoids, hormone replacement therapy, benzodiazepines).

2.2. Diagnostic instruments

A standardized psychiatric examination validated within the French general population

(Lecrubier et al., 1997); the Mini International Neuropsychiatric Interview MINI (French version

5.00), was used to detect psychiatric symptomatology according to DSM-IV criteria (American

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Psychiatric Association, 1994).

2.3. Cortisol measurement

Subjects were instructed not to drink, eat or smoke for at least 30mn before saliva collection

and to start the protocol at least 1h after awakening (mean time 1.5+0.8h) and subsequently twice

with a 6-7h interval (the last sample being collected before midnight), recording the exact time.

Mean values for sampling were 8.8+0.3, 15.7+0.7 and 21.7+0.6h.

Cortisol levels were determined from saliva collection (Hellhammer et al., 1987) by direct

radioimmunoassay (Diagnostic Systems Laboratories-Webster, Texas). For less than 5% of the

samples, the values were lower than the detection limit (10ng/dl) and were replaced by a value

corresponding to the threshold value divided by two. When adequate volume could not be

provided subjects were excluded from the analysis. Thirty six subjects with an atypical cortisol

baseline profile (flat pattern or abnormal time peak) were excluded from the sample. The present

study has been conducted on 201 subjects showing a typical pattern at baseline.

2.4. Baseline and environmental stress conditions

Subjects were allowed to decide wake up and sleep times and to collect samples when

convenient. Participants were encouraged to carry on their normal daily activities with limited

physical exertion in order to maximize ecological validity. Samples were taken at the hospital

(“stressful situation”) where a lengthy clinical examination (between 08-11h AM) was undertaken

involving recognized psychosocial stressors, (e.g. psychiatric examination, cognitive testing,

clinical evaluation, blood collection), and a subsequent quiet day at home (baseline condition).

2.5. Statistical analysis

Since the distribution of raw cortisol is typically skewed and the diurnal profile may be

approximated by an exponential curve, raw values were log-transformed1. Given the non-fixed

time sampling protocol, AUC were standardized and calculated by trapezoidal estimation between

1 An absolute difference (δ) between two LnC values thus corresponds to a (e δ−1) x100 variation (expressed as %)

on initial (non log-transformed) cortisol concentrations.

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08h and 22h for each subject (extrapolating values from the equation of the regression line of the

three-cortisol values on the hour of sample collection). Group comparisons were carried out using

Student’s t-test and analysis of variance for categorical explanatory variables. Individual stress

responses comparing home and hospital cortisol values were performed using paired t-tests.

Comparison of cortisol profiles on stressful and basal situations was also carried out using a

hierarchical mixed model. This takes into account individual differences, differences with time

within the day and differences between days (3 levels). Anxiety disorders were entered

individually into the model to assess their impact on differences in cortisol levels between the two

sampling days. Time was entered both as a fixed and random effect, allowing for individual

random differences form the sample mean cortisol value according to time of day.

All analyses were stratified by sex. p values <0.05 were considered to be statistically

significant. Data were analyzed using SAS version 8.2 (Cary, NC).

3. Results

Subject characteristics are shown in Table 1. Cortisol concentrations and AUC were higher

and slope flatter in women, however no age effect was observed (data not shown).

3.1. Diurnal cortisol and anxiety disorder in women

Women with and without lifetime GAD did not differ on baseline measures (Table 2A).

Following stress, paired comparisons indicate an increase in AUC and LnC, which was significant

at 15h and 22h, for both groups. Group comparisons showed that on the stressful day LnC at 15h

and 22h and AUC were significantly higher in women with GAD (by 7.9%, 12.6% and 8%,

respectively) as also suggested examining relative differences. A similar pattern was observed for

the 21 women reporting lifetime phobia (data not shown). Mixed models further indicate a

significant interaction between sampling day and GAD (F=8.36, p=0.004) or phobia (F=6.79,

p=0.009).

For all lifetime anxiety disorders, a gradual increase in AUC, LnC15h, and LnC22h and slope

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flattening were observed on the stressful day along with the number of associated anxiety

symptoms (p<0.001) (data not shown). Subjects with current anxiety disorders (n=17) showed

similar patterns to those with past anxiety disorders.

While only one woman reported lifetime PTSD, eight women reported previous severe

trauma with subsequent distressing intrusions ("traumatized" group), thus meeting criteria A and B

for DSM-IV PTSD. Their AUC, LnC15h, and LnC22h were significantly lower at baseline (by 13.3,

13.3, and 31.6%, respectively) and the slope steeper (by 43.8%) compared to “non-traumatized”

women (Table 2B). No differences were observed on the stressful day between “traumatized” and

“non-traumatized” women, suggesting the former had developed an efficient compensatory

response (see relative differences or paired comparisons). Mixed models indicate an interaction

between sampling day and trauma with intrusions (F=4.59, p=0.03). The value for the interaction

between time and sampling day was significant only for "traumatized" subjects (F=4.69, p=0.038)

and that between time and trauma for the day at home only (F=5.45, p=0.022).

3.2. Diurnal cortisol and anxiety disorder in men

No significant differences between men with and without lifetime anxiety disorder were

observed on the baseline measure. In the stressful situation, slope was flatter (by 22.2%, p=0.01),

LnC22h higher (by 11.1%, p=0.04), and ΔLnC8h lower (p=0.04) in the anxious than in the

non-anxious group (data not shown). Mixed models indicate an interaction between time and day

which was significant only for subjects reporting lifetime anxiety disorders (F=4.97, p=0.029) and

between time and anxiety for the hospital-day only (F=7.07, p=0.009).

In men with a history of trauma with intrusions, LnC8h tended to be higher by 7.4%

(p=0.07) and slope steeper by 29.4% (p=0.07) compared to “non-traumatized” men suggesting a more rapid decline rate under baseline conditions. A high increase was observed in ΔLnC22h

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(52.2% compared to 17.2% in controls, p=0.01), giving recovery levels after stressful situation

similar to that of the "non-traumatized" group. Mixed models suggested a time/trauma interaction

(at home) and a time/day interaction in "traumatized" subjects .

4. DISCUSSION

4.1. Methodological considerations and study design

This naturalistic study explored the effect of exposure to a common stressful situation in the

morning on subsequent diurnal cortisol levels at home. Our findings are more directly comparable

to “post-event processing” i.e. the prolonged cognitive processing period following social

interaction (Fehm et al., 2007) than to "recovery period" studies conducted 1-2h after pre-test

basal cortisol evaluation (Kudielka et al., 2004; Seeman et al., 1995).

In subjects both with and without psychiatric disorder, enhanced cortisol levels were

observed from 4h to 11h after the stressful situation. No study has investigated long-term activity

of the HPA axis following stress, notably during the “post-event processing” period. However,

delayed recovery and sustained recurrent elevations in physiological autonomic nervous system

responses to emotional tasks have been observed in healthy adults, partly related to ruminations

(Glynn et al., 2002). Ruminations, which may last several days after social exposure (Fehm et al.,

2007), are an important psychological component of anxiety whose effect may be exacerbated in

the elderly.

4.2. Anxiety disorder and exposure to environmental stress

Lifetime anxiety disorder in this community sample is common (27%). Subjects with

anxiety disorder show baseline cortisol levels similar to those without anxiety disorder. Men with

anxiety disorders showed a secretion increase following stressful situation, but with a slower

decline rate compared to non-anxious men. In women a dose-effect was observed; the higher the

anxiety co-morbidity, the greater the increase in total secretion and the lower the recovery capacity

following the stressful situation.

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Cortisol secretion in anxious subjects under stress conditions has only been evaluated in

young adults, generally during an acute stressful challenge, with inconsistent results. Condren et al

found an increase in cortisol secretion in patients with phobia compared to controls but not during

the 90 mn recuperation period (Condren et al., 2002). Furlan et al reported that phobic patients

responded less frequently to psychosocial stress than controls, but with a higher increase in

cortisol secretion on a stress-test (Furlan et al., 2001). Young et al reported normal cortisol

responses to the Trier Social Stress Test in subjects with pure anxiety or pure mood disorders,

whereas they observed a greater ACTH and cortisol (trend) response to the stressor, in depressed

subjects with co-morbid anxiety (Young et al., 2004a). In our study the proportion of subjects

reporting current anxiety disorder with co-morbid major depression was too low (0.5%) to affect

the results. For lifetime anxiety disorder, the same cortisol pattern was observed irrespective of

depression co-morbidity (unpublished data).

4.3. Sub-syndromic PTSD

In everyday functioning, elderly traumatized persons have continuous basal low cortisol

levels with a more rapid decline than controls. Following stress, accelerated secretion was

observed to reach “normal” levels of cortisol excretion. This pattern is specifically associated with

PTSD intrusive symptoms, suggesting that both intrusions and cortisol changes could be

indicative of trauma severity.

Low cortisol concentration in PTSD has been frequently reported (Boscarino, 1996; Mason

et al., 1986; Neylan et al., 2005; Rasmusson et al., 2003; Yehuda, 2001; Yehuda et al., 1995)

although not systematically (Baker et al., 2005; Maes et al., 1998; Pitman and Orr, 1990; Young et

al., 2004b). In our sub-syndromic group with intrusive symptoms, we found a similar pattern of

lowered cortisol secretion at baseline suggesting a continuum with PTSD. Low cortisol

concentration has also been reported in non-PTSD subjects living under conditions of

chronic/prolonged stress (maintained by intrusions and recurrent memories (Baum et al., 1993))

which may modify HPA axis functioning (Hellhammer and Wade, 1993). Our observations are

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compatible with this theory. Response increase in the stressful situation suggests efficient HPA

axis reactivity (Yehuda et al., 1996).

Recent studies have demonstrated that glucocorticoid administration can inhibit the

expression of PTSD symptoms in young adults (Schelling et al., 2004a; Schelling et al., 2004b),

notably intrusive symptoms (Aerni et al., 2004) by inhibiting excessive retrieval of traumatic

memories (Aerni et al., 2004; de Quervain et al., 1998; de Quervain et al., 2000). Our findings of

low cortisol levels related to intrusive symptoms support these observations. Evaluating

glucocorticoid treatment in subjects with low basal cortisol could thus be an alternative to

psychotropic medication (Schuder, 2005).

4.4. Limitations and strength

Although this population study had to be limited to 3-salivary measures, the basal

characteristics of cortisol secretion are similar to previous studies with more frequent sampling

(Ice et al., 2004). The random selection of subjects, the systematic return of saliva samples by all

subjects and the choice of a non-fixed time sampling protocol (known to improve compliance

(Jacobs et al., 2005)), suggest our findings to be representative of naturalistic conditions.

However, one limitation could be that the current anxiety syndromes may have been less severe as

benzodiazepine use constituted an exclusion criterion. We aimed to examine differences between

baseline and naturalistic exposure to stress rather than to a single experimental stressor;

randomization of days not being feasible, we commenced with stress exposure, thus obtaining

maximal contrasting conditions (avoiding novelty/anticipatory effects on baseline measures). We

also controlled for eating, drinking, smoking, and physical exertion. Subjects did not report any

particular potential additional stressors on the day they performed sampling. Although our study

could be considered exploratory, the differences observed more likely result from the effect of

anxiety disorders on the response to the stressor. Despite multiple analyses, Bonferroni corrections

were not considered necessary, the patterns of cortisol changes being consistently observed for

both sexes and using both general linear and hierarchical mixed model analyses.

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4.5. Implications of the study

In normal everyday functioning elderly persons have a pattern of daytime cortisol secretion,

which is not affected by either age or anxiety disorders. Everyday stress induces a higher increase

in cortisol secretion in persons with anxiety disorders than in non-anxious persons, and slower

recovery rates, probably related to post-event processing. Women appear more reactive to stressful

environmental conditions than men, perhaps explaining their overall heightened vulnerability to

anxiety disorders. Similar changes were observed in subjects with past anxiety disorder suggesting

this vulnerability to be a stable trait. A similar pattern of alteration is observed in anxiety disorders

when taken together or by sub-type (phobias or GAD), suggesting a common "core" with respect

to HPA axis dysregulation. Rate of increase in cortisol secretion may also be a putative marker of

anxiety severity (associated with increased co-morbidity). Do these differences in HPA axis

physiology constitute individual vulnerability to psychopathology? Follow-up studies are required

to further examine the relationships between HPA axis changes and time of onset of

psychopathology.

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Table 1

General characteristics of the cortisol study participants

Subjects (N =201)

Female gender (%) 43.8

Mean age (SD) 72.9 (4.5)

Low Education levela (%) 47.3

Current Smoking 6.0

MMSE score below 24 (%) 4.5

Body Mass Index in kg/m2 (mean (SD)) 25.6 (3.6) CURRENT MAIN PSYCHIATRIC DISORDERS

Major Depressive Episode (%) 1.0

Generalized Anxiety Disorder (%) 3.0

Phobia (%) 10.1

PTSD (%) 0.5

At least one anxiety disorder (%) 13.7

Current comorbidity (Anxiety disorder + MDE) (%) 0.5 LIFETIME MAIN PSYCHIATRIC DISORDERS

Major Depressive Episode (%) 18.4

Generalized Anxiety Disorder (%) 11.1

Phobia (%) 17.4

Severe trauma (DSM-IVb) (%) 29.9

Sub-syndromic PTSD (DSM-IVb) (%) 9.1

PTSD (%) 1.5

At least one anxiety disorder (%) 26.9

Comorbidity (Anxiety disorder + MDE) (%) 10.1 a

Corresponding to 9 years of schooling or less. b

Sub-syndromic PTSD corresponds to subjects meeting criteria A and B for DSM-IV PTSD, i.e. having reported previous severe trauma with subsequent distressing intrusions.

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Table 2: Cortisol levels under basal and stressful conditions for women according to the absence (0) or presence (1) of anxiety disorder. 2A: Lifetime GAD

GROUP COMPARISONS PAIRED COMPARISONS

Baseline Stress Relative difference (Δ)**

Cortisol parameters GAD (0: n=68) (1: n=18) mean SD p mean SD p % p p 0 5.53 0.59 5.67 0.67 3.6 0.09 LnC8h* 1 5.63 0.68 0.51 5.97 0.76 0.11 7.2 0.35 0.13 0 4.38 0.62 4.58 0.51 5.8 < 0.001 LnC15h* 1 4.38 0.65 0.97 4.94 0.62 0.01 14.4 0.01 0.001 0 3.24 0.97 3.48 0.74 17.9 0.01 Ln22h* 1 3.13 1.05 0.65 3.92 0.88 0.03 37.6 0.10 0.002 0 -0.16 0.07 -0.16 0.07 14.5 0.49 slope 1 -0.18 0.09 0.43 -0.15 0.08 0.59 1.4 0.49 0.17 0 61.39 8.62 64.08 7.14 5.8 < 0.001 AUC 1 61.30 9.05 0.97 69.21 8.69 0.01 14.4 0.01 0.001

2B: Lifetime Traumatism and Intrusions

GROUP COMPARISONS PAIRED COMPARISONS

Baseline Stress Relative difference (Δ)

Cortisol parameters Trauma + Intrusions (0: n=78) (1: n=8) mean SD p mean SD p % p p 0 5.56 0.60 5.76 0.72 4.4 0.03 LnC8h 1 5.43 0.71 0.56 5.53 0.35 0.38 3.0 0.80 0.70 0 4.44 0.60 4.68 0.57 6.6 <0.001 LnC15h 1 3.85 0.59 0.01 4.44 0.35 0.24 17.3 0.03 0.03 0 3.32 0.95 3.59 0.80 17.3 0.002 LnC22h 1 2.27 0.81 0.003 3.34 0.59 0.39 67.7 0.002 0.02 0 -0.16 0.07 -0.15 0.07 15.0 0.50 slope 1 -0.23 0.07 0.02 -0.16 0.05 0.95 -19.9 0.18 0.06 0 62.12 8.37 65.46 7.91 6.6 <0.001 AUC 1 53.85 8.31 0.01 62.11 4.96 0.24 17.3 0.03 0.03

*Time concentrations correspond to the Ln of cortisol concentration expressed as ng/dl. **Corresponds to the mean of the ratios [(hospital – home)/ home] expressed as %.

Figure

Table 2: Cortisol levels under basal and stressful conditions for women according to the absence (0) or presence (1) of anxiety disorder

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